The brain is one of the largest and most complex organs of the body. It controls all aspects of sensory and motor function in the body and the intellectual functions of memory and reason. The brain may be divided into three major areas based on embryologic origin: the forebrain, which includes the two cerebral hemispheres and the cerebral cortex; the midbrain, which includes the corpora quadrigemina, tegmentum, and cerebral peduncles; and the hindbrain, which includes the cerebellum, pons and medulla. Different regions of the brain are associated with different functions, although attributing specific functions to definite regions of the brain is not entirely accurate, since many activities may be performed in several different regions. (See McNance, K. L. and Huether, S. E. (1994) Pathophysiology: The Biologic Basis for Disease in Adults and Children, 2nd Ed, Mosby-Yearbook, Inc, St Louis, Mo., pp. 404-410.)
Disorders of the brain include cancers of the brain (gliomas); dementia, such as Alzheimer's disease resulting from the loss of acetylcholine-transmitting neurons distributed throughout the brain; Parkinson's disease caused by depletion of dopamine in the substantia nigra and basal ganglia; Huntington's disease which appears to be related to a severe loss of striated neurons; epileptic seizures which may result from a number of systemic and cerebral disorders that can affect cortical function; and schizophrenia characterized by hallucinations, delusions, and disorganized thought and behavior. (Robbins, S. L. et al. (1994) Pathologic Basis of Disease: 5th Ed, W.B. Saunders Co., Philadelphia, Pa., pp. 1329-1335, and 1342-1346.)
Some of these disorders have definite genetic associations and genetic predispositions. The gene associated with Huntington's disease has been localized to the chromosome region 4p6.3. Early-onset familial Alzheimer's disease includes at least three gene defects on chromosomes 14, 19, and possibly 21. (McNance, supra, p504.) Schizophrenia has likewise been linked to chromosome region 22q11-13, and a genetic predisposition to this disease is well established. (Coon, H. et al. (1994) Am. J. Med. Genet. 54:59-71; and Karayiorgou, M. et al. (1995) Proc. Natl. Acad. Sci. 92:7612-7616.) Various brain-specific proteins, including the somatostatin receptor, SSTR3, have been mapped to the 22q11-13 region as well. (Yamada, Y. et al. (1993) Genomics 15:449-452.)
Somatostatin (SS) is a small (14 amino acids) neuropeptide originally discovered as a hypothalmic inhibitor of pituitary hormone release. It was subsequently found to be widely distributed in the body, in the central nervous system, and in several peripheral tissues such as stomach and intestine. SS has additional biological functions as a modulator of various endocrine and exocrine secretion processes. In the central nervous system, SS functions as a neurotransmitter and may be an important regulator of motor activity and cognitive processes. In addition, SS shows antiproliferative effects in vivo and in vitro and may be an important modulator of cell proliferation. (Rohrer, L. et al. (1993) Proc. Natl. Acad. Sci. 90:4196-4200.) Furthermore, in some neurodegenerative disorders such as Alzheimer's and Parkinson's disease, significant decreases have been noted in cerebral cortical SS.
The diversity in biological activity of SS is mediated through a family of G-protein coupled receptors, individual members of which have different pharmacological properties and are expressed in a tissue-specific manner. (Rohrer, L. et al. supra; Yamada, Y. et al. (1992) Proc. Natl. Acad. Sci. 89:251-255.) Somatostatin receptor 4 (SSTR4), for example, is a brain-specific SSTR that appears to act in a signal transduction pathway that involves G-protein interactions and activation of a MAP-kinase cascade. (Bito, H. et al. (1994) J. Biol. Chem. 269:12722-12730.)
All of the SSTR family members are transmembrane receptors with multiple transmembrane domains. They also share other structural features such as one or more N-glycosylation sites, which may be involved in high-affinity ligand binding, and various arrangements of phosphorylation sites that are believed to couple individual receptors to multiple effector systems. (Rohrer et al., supra.)
The discovery of a new human brain-associated protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of neurodegenerative disorders and cancer.